Compounds (I) above are known as key intermediates in the synthesis of iodinated contrast agents.
U.S. Pat. No. 4,001,323 for instance describes a process for the preparation of iopamidol (II)

by iodination of a compound (I) wherein R is a group —CH(CH2OH)2, followed by acylation of the 5-amino group by a suitably selected chiral acylating agent.
U.S. Pat. No. 4,250,113 on the other hand discloses a similar process for the preparation of iohexol (III),

by iodination of a compound (I) wherein R is —CH2—CH(OH)—CH2OH, acetylation of the 5-amino group, and N-alkylation of the resulting 5-acetamido group to yield the compound (III).
In the literature the compounds of formula (I) above are prepared starting from 5-nitro-1,3-benzenedicarboxylic acid dimethyl ester,

by amidation of the ester groups with 2-amino-1,3-dihydroxypropane (a compound of formula H2N—CH(CH2OH)2 commonly known as serinol) or with 1-amino-2,3-dihydroxypropane (of formula H2N—CH2—CHOH—CH2OH commonly known as isoserinol), followed by reduction of the 5-nitro group of the thus obtained N,N′-bis-substituted 5-nitro-1,3-benzenedicarboxamides (IV),

wherein R is as defined above, to 5-amino to yield the desired products (I).
The amidation reaction in said processes is typically carried out with at least the stoichiometric amounts of serinol or isoserinol (i.e. at least two moles of serinol or isoserinol per mol of 5-nitro-1,3-benzenedicarboxylic acid dimethyl ester), in the presence of a protic organic solvent, such as a lower alkanol, and at a temperature of from about 65° C. to about 150° C.
The intermediate product (IV) is then isolated and hydrogenated in the presence of a suitable hydrogenation catalyst, such as Pd/C to yield the product (I).
An improvement to the above general method has recently been described, in WO 00/29372. The method there described involves carrying out the amidation reaction on the 5-nitro-1,3-benzenedicarboxylic acid lower alkyl esters in an organic solvent, typically a lower aliphatic alcohol, in the presence of a strong basic catalyst and then, without isolating the intermediate N,N′-substituted-5-nitro-1,3-benzenedicarboxamide (IV), catalytically hydrogenating the reaction solution to get the desired product (I). Also in this case the temperature reported for the amidation of the 5-nitro derivative is from about 65° C. to 150° C., depending on the type of solvent employed.
It has however been found that the products obtained through amidation of the 5-nitro-1,3-benzenedicarboxylic acid alkyl esters with 2-amino-1,3-dihydroxypropane or with 1-amino-2,3-dihydroxypropane, i.e. the compounds of formula (IV), are products that must be handled with great care, for their characteristic instability. Specific differential scanning calorimetry (DSC) tests have in fact demonstrated that these compounds are not stable at high temperatures even if maintained in solution. More particularly said DSC tests have shown that brought at a temperature of 120° C. the compounds of formula (IV) start decomposing with the emission of fumes. The poor stability of the 5-nitro 1,3-benzenedicarboxamides (IV) at high temperatures may drastically limit the choice of the reaction conditions that need to be strictly controlled particularly on industrial scale to prevent possible safety and pollution problems. It may also negatively affect the yields theoretically obtainable in the overall process.
There is therefore a need for an improved process that might allow to obtain the intermediate compounds (I) with high yields under reaction conditions that are easily applicable in an industrial process and where no stability problems may arise.
The process according to the present invention meets said need.
It has been found, in fact, that it is possible to obtain a compound of formula (I) in high yields also by direct amidation of a dialkyl ester of 5-amino-1,3-benzenedicarboxylic acid and that no stability problems do arise in connection with the dialkyl ester of 5-amino-1,3-benzenedicarboxylic acid or with the 5-amino-N,N′-bis-substituted-1,3-benzenecarboxamides (I) thus allowing the reaction to be carried out industrially under widely varying conditions.